Facial and other skin lines and wrinkles develop through a combination of aging, heredity, muscle action, sun damage and gravity. Facial and other skin expressions are made by strong muscle contractions, and over time, create skin wrinkles such as forehead lines, crow's feet and the vertical creases between the eyes. Wrinkles mostly result from a strong muscular contraction or from a prolonged time in this position. At the cellular level, the fibroblast cells synthesizing the extracellular matrix and collagen that are located along the tension lines could under the effect of muscular contractions develop particular contractile properties related to striated muscle.
The junction between a nerve and striated muscle constitutes the neuromuscular plates, upstream of which is the afferent nerve pathway, known as the motor neuron.
Muscle contraction is caused by acetylcholine, a neurotransmitter. Acetylcholine is released by the nerve that stimulates the muscle. It is known that the skin muscles of the face are under control of motor nerve afferences, and the hypoderm contains fine, flat sheets of striated muscle called the panniculus carnosus that constitute muscle tissue.
Today such mimic and age-related wrinkles are often treated with Botox (Botulinum toxin A, produced by the pathogenic microorganism Clostridium botulinum). Botox acts by preventing the release of acetylcholine. This toxin temporally paralyzes the muscle and inhibits contraction. Absences of contractions prevents wrinkles and induces a smooth and rejuvenated skin. Such toxins act as proteases, more specifically zinc endopeptidases targeting the neuronal cytosol: Botox B, D and F, as well as tetanus toxin produced by the Clostridium tetani pathogenic microorganism attack specifically VAMP (also called synaptobrevin)—a protein of synaptic vesicles; Botox A and E cleave SNAP-25 and Botox C acts on syntaxin—both proteins of the presynaptic membrane (See for example Proc. West. Pharmacol. Soc. 43: 71-74, 2000.
Botox is injected locally in tissues which are thereby paralyzed. The muscles at the eyes or at the forehead don't operate any more, making the apparition of a forehead wrinkle difficult if not impossible. However, the fact that the treatment with subcutaneously injected Botox has to be conducted by a physician, its consequently high costs and its extremely high toxicity constitute considerable disadvantages. Its effectiveness lasts from 3 to 6 months, whereupon the treatment has to be repeated.
It is known from the European patent applications EP 2123673 and EP 1180524 under the name of Lipotec that peptides comprising an amino acid sequence derived from the amino acid sequence of the protein SNAP25 can compete with SNAP 25 by mimicking its IM-terminal end and thus interfering in the SNARE complexes. If the SNARE complexes are destabilized, the synaptic vesicles cannot release acetylcholine efficiently and muscle contraction can be altered.
The mechanism of action of these peptides is similar to that of botulinum toxins focusing on inhibition of neuronal exocytosis of acetylcholine.
El Far Oussama and col. In Patent application WO 2011/448441 in the name of INSERM describes direct molecule interaction between VATPase and SNARE synaptobrevin (VAMP2). Soluble peptides with sequence corresponding to a portion of a VATPase subunit have the property to interfere with the neurotransmitter release.
Patent application WO 2009/012376 IN THE NAME OF University of OHIO STATE RES FOUND refers to opioid receptors that have been identified in peripheral processes of sensory neurons. Peptides have been used as delta opioid receptor agonists. This binding with the receptors inhibits the release of GABA from the nerve terminal, reducing the inhibitory effect of GABA on dopaminergic neurons.
Other peptides that are able to acts in a manner similar to Waglerin 1, a snake venom protein, acting at the post-synaptic membrane, as antagonist of the muscular nicotinic acetylcholine receptor are described in patent application WO 2006/047900 in the name of Pentapharm.
Moreover, cell membranes comprise numerous ion channels. Molecules acting as calcium channels inhibitors are for example described in the US patent application 2008/0050318 in the name of L'OREAL.
These calcium channels can be found in human fibroblasts, see for example J. Biol. Chem 267; 10524-10530, 1992 and Science 230 1024-1026, 1988.
Original peptides isolated from the venom of marine snails belonging to the family of mu-conotoxin or mu-conopeptides and acting as sodium channel inhibitors have been described in patent applications WO 2004/099238, WO 2002/07678, US 2003/050234 or WO 2007/054785. Voltage sensitive channels are key components for generating action potentials in electrically excitable cells by forming the action potential upstroke. A great diversity of sodium ion channel types and sub-types exist. All of them are voltage-sensitive sodium channel (VSSC) which open and then close in response to membrane depolarization.
The mu-conopeptides from venoms of the marine snails are able to block VSSC by blocking directly action potentials in sciatic and olfactory nerves of mouse and pike, for example. The resulting pharmacological effect consists in a block of conductance, leading to loss of function of neuromuscular system as described in the patent application WO 2007/054785 in the name of ATHERIS.
Based on their susceptibility to be blocked by tetrodotoxin (TTX), VGSCs can be divided into tetrodotoxin sensitive (TTX-S) and TTX-resistant (TTX-R) classes. These include the neuronal TTX-S type 1/Nav1. 1, lilNav1. 2 III/Nav1. 3, PN1/Nav1.7 and PN4/Nav1.6, and the skeletal muscle TTX-S u1/Nav1.4.
Mu-conopeptides target a variety of voltage sensitive sodium channel, blocking primarily the Navl.4 channel.
To date, no inhibitory activity on sodium channel for cosmetic application has been described or suggested for these peptides.